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Trial record 1 of 3 for:    ICON | Breast Cancer | Norway
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Phase IIb Study Evaluating Immunogenic Chemotherapy Combined With Ipilimumab and Nivolumab in Breast Cancer (ICON)

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ClinicalTrials.gov Identifier: NCT03409198
Recruitment Status : Recruiting
First Posted : January 24, 2018
Last Update Posted : March 12, 2018
Bristol-Myers Squibb
Helse Stavanger HF
Helse Sor-Ost
Sorlandet Hospital HF
Information provided by (Responsible Party):
Jon Amund Kyte, Oslo University Hospital

Brief Summary:
Breast cancer is rarely curable after metastasis, and the therapeutic options are limited. Interestingly, the host immune response is strongly predictive for the effect of chemotherapy in subgroups of patients with breast cancer. The aim is to release the brake on the immune response by use of ipilimumab, which blocks CTLA-4 and may deplete regulatory T cells, combined with nivolumab (anti PD1). Importantly, it is possible that non-responders to nivolumab/ipilimumab (nivo/ipi) can be turned responders by use of immunogenic chemotherapy.

Condition or disease Intervention/treatment Phase
Breast Cancer Luminal B Drug: Ipilimumab Drug: Nivolumab Drug: Pegylated liposomal doxorubicin Drug: Cyclophosphamide Phase 2

Detailed Description:
There is compelling evidence from animal studies, supported by data from humans, that some chemotherapeutic agents are immunogenic. Doxorubicin and cyclophosphamide have been shown to be particularly powerful inducers of immunogenic cell death. Both agents fulfil 5/5 criteria established for assessing the immunogenicity of different chemotherapeutic drugs. There is also strong evidence from humans, particularly in breast cancer, indicating that the clinical effect of doxorubicin and cyclophosphamide depends on the host immune response. Further, these agents have been shown to induce a Type I interferon immune response in breast cancer. Taken together, there is a strong rationale for synergy between doxorubicin/cyclophosphamide and PD-1/CTLA-4 blockade. The trial combines nivolumab and ipilimumab with established 1st choice chemotherapy in patients with metastatic luminal B breast cancer. Nivolumab/ipilimumab (nivo/ipi) may i) potentiate the patient´s spontaneous anti-tumor immune response ii) synergize with chemotherapeutic agents that induce immunological cell death

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 75 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized, open-label
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase IIb Study Evaluating Immunogenic Chemotherapy Combined With Ipilimumab and Nivolumab in Patients With Metastatic Luminal B Breast Cancer
Actual Study Start Date : January 21, 2018
Estimated Primary Completion Date : January 1, 2022
Estimated Study Completion Date : January 1, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
U.S. FDA Resources

Arm Intervention/treatment
Active Comparator: Arm A
Chemo only (pegylated liposomal doxorubicin + cyclophosphamide)
Drug: Pegylated liposomal doxorubicin
Drug: Cyclophosphamide
Experimental: Arm B
Chemo + ipilimumab + nivolumab
Drug: Ipilimumab
Ipilimumab blocks CTLA-4 and may deplete regulatory T cells
Other Name: Yervoy
Drug: Nivolumab
Nivolumab blocks PD-1 and thereby enhances the effector phase of the immune reaction, by enabling T cells to kill tumor cells and engage effectively with other PD-L1 expressing targets.
Other Name: Opdivo
Drug: Pegylated liposomal doxorubicin
Drug: Cyclophosphamide

Primary Outcome Measures :
  1. Toxicity: CTCAE v4.0 [ Time Frame: 3 years ]
    Assessment of toxicity of combined treatment with ipilimumab, nivolumab, pegylated liposomal doxorubicin and cyclophosphamide (ipi/nivo/chemo)

  2. Progression-free survival (PFS) [ Time Frame: We expect to reach the data-driven time point for PFS-analysis (95% PFS in the control group) approximately 3 years after the study opens. If this is not met within 24 months after inclusion of the last patient, the PFS-analysis will be performed at this ]
    Assessment of clinical response in ipi/nivo/chemo group compared to chemo only group: Progression-free survival (PFS); compare the PFS rates when 95% of patients in the control croup have PD

Secondary Outcome Measures :
  1. Duration of Response (DR) [ Time Frame: 3 years ]
    Assessment of clinical response in ipi/nivo/chemo group compared to chemo only group: duration of response (DR)

  2. Overall Survival (OS) [ Time Frame: 5 years ]
    Assessment of clinical response in ipi/nivo/chemo group compared to chemo only group: overall survival (OS)

  3. Duration of Response (DR) in cross-over arm [ Time Frame: 3 years ]
    Assessment of clinical response in ipi/nivo group: duration of response (DR)

  4. Overall Suvival (OS) in cross-over arm [ Time Frame: 5 years ]
    Assessment of clinical response in ipi/nivo group: overall survival (OS)

  5. Toxicity, cross-over arm, CTCAE v4.0 [ Time Frame: 3 years ]
    Assessment of toxicity of ipi/nivo (without chemotherapy) in cross-over arm

  6. Objective tumor Response Rate (ORR) [ Time Frame: 3 years ]
    Assessment of clinical response in ipi/nivo/chemo group compared to chemo only group: Objective tumor response rate (ORR)

  7. Durable tumor Response Rate (DRR) [ Time Frame: 3 years ]
    Assessment of clinical response in ipi/nivo/chemo group compared to chemo only group: durable tumor response rate (DRR; >6 months)

  8. Objective tumor Response Rate (ORR) in cross-over arm [ Time Frame: 3 years ]
    Assessment of clinical response in ipi/nivo group: Objective tumor response rate (ORR)

  9. Durable tumor Response Rate (DRR) in cross-over arm [ Time Frame: 3 years ]
    Assessment of clinical response in ipi/nivo group: durable tumor response rate (DRR; >6 months)

Other Outcome Measures:
  1. Immunological response [ Time Frame: 3 years ]
    Assessment of immunological response

  2. Biomarkers for clinical response [ Time Frame: 3 years ]
    Identification of biomarkers for clinical response by use of gene profiling, pathology, cytokine assays and other analysis on material from study patients

  3. Biomarkers for toxicity [ Time Frame: 3 years ]
    Identification of biomarkers for toxicity by use of gene profiling, pathology, cytokine assays and other analysis on material from study patients

  4. Chalder Fatigue Questionnaire (FQ) [ Time Frame: 3 years ]
    Assessment of patient reported outcomes, as measured by the Chalder Fatigue Questionnaire (FQ)

  5. Pain intensity [ Time Frame: 3 years ]
    Assessment of patient reported outcomes, as measured by an 11 point Numerical Rating Scale (NRS) for pain intensity

  6. EORTC QLQ-C15-PAL [ Time Frame: 3 years ]
    Assessment of patient reported outcomes, as measured by the EORTC QLQ-C15-PAL

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Metastatic hormone receptor positive breast cancer (primary or recurrent), defined as ER+ >1% in metastatic biopsy (archival material or study biopsy) and HER2 negative in the last biopsy evaluable for HER2. HER2-analysis is to be perfomed according to national criteria.
  2. Luminal B breast cancer
  3. Adequate core or excisional study biopsy of a metastatic tumor lesion not previously irradiated. No anti-tumor treatment is allowed between the time point for biopsy and study entry.
  4. Measurable metastatic disease according to RECIST
  5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  6. Signed Informed Consent Form
  7. Women or men aged ≥ 18 years
  8. A minimum of 24 months since adjuvant/neoadjuvant chemotherapy with antracyclins
  9. A maximum of one previous line with chemotherapy in the metastatic setting
  10. Chemotherapy is considered as preferred treatment
  11. Previous endocrine and targeted therapy is allowed
  12. No use of systemic corticosteroids at study entry
  13. Female subject of childbearing potential should have a negative urine or serum pregnancy within 7 days prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  14. Female subjects of childbearing potential should agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year, during the treatment period and for at least 5 months after the last dose of study therapy.
  15. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 7 months after the last dose of study therapy
  16. Adequate organ function as defined in Table 1

Exclusion Criteria:

  1. Malignancies other than breast cancer within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer)
  2. Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for > 8 weeks prior to randomization
  3. Known CNS disease, except for treated asymptomatic CNS metastases, provided all of the following criteria are met:

    1. Measurable disease outside the CNS
    2. Asymptomatic for CNS disease > 4 months.
    3. Only supratentorial metastases allowed
    4. No evidence of progression after completion of CNS-directed therapy
    5. No ongoing requirement for dexamethasone as therapy for CNS disease
    6. No radiation of brain lesions within 4 months prior to randomization
    7. No leptomeningeal disease
  4. Known BRCA mutation, unless the patient has already received carboplatin or for other reasons should not receive carboplatin treatment, according to own preferences or reccommendations by the treating physician.
  5. Uncontrolled pleural effusion, pericardial effusion, or ascites. Patients with indwelling catheters (e.g., PleurX®) are allowed
  6. Uncontrolled tumor-related pain. Patients requiring narcotic pain medication must be on a stable regimen at study entry. Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to randomization. Asymptomatic metastatic lesions whose further growth would likely cause functional deficits or intractable pain (e.g., epidural metastasis that is not presently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to randomization
  7. Ionized calcium > 1.2 x UNL. The use of bisphosphonates is allowed
  8. Pregnant or breastfeeding
  9. Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome)
  10. Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction within 3 months prior to randomization, unstable arrhythmias, or unstable angina Patients with a known left ventricular ejection fraction (LVEF) < 40% will be excluded. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate
  11. Severe infection within 21 days prior to randomization, requiring hospitalization
  12. Received oral or IV antibiotics within 1 week prior to Cycle 1, Day 1. Patients receiving routine antibiotic prophylaxis (e.g., to prevent chronic obstructive pulmonary disease exacerbation or for dental extraction) are eligible
  13. Major surgical procedure within 21 days prior to randomization or anticipation of the need for a major surgical procedure during the course of the study other than for diagnosis. Placement of central venous access catheter(s) is not considered a major surgical procedure and is therefore permitted
  14. A history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  15. Known hypersensitivity to any of the components of the investigational products
  16. A history of autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxin, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only (e.g., no psoriatic arthritis) are permitted provided that they meet all of the following conditions:

    1. Rash must cover less than 10% of body surface area.
    2. Disease is well controlled at baseline and only requiring low potency topical steroids
    3. No acute exacerbations of underlying condition within the last 12 months (not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, high potency or oral steroids)
  17. Undergone allogeneic stem cell or solid organ transplantation
  18. A history of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
  19. A positive test for HIV
  20. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
  21. Active tuberculosis
  22. Currently receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
  23. Received treatment with immune checkpoint modulators, including anti−CTLA-4, anti−PD-1, or anti−PD-L1 therapeutic antibodies
  24. Received treatment with systemic immunostimulatory agents (including but not limited to interferons or IL-2) within 4 weeks or five half-lives of the drug (whichever is shorter) prior to randomization
  25. Received treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor [TNF] agents) within 2 weeks prior to randomization, or anticipated requirement for systemic immunosuppressive medications during the trial

    1. Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study
    2. Patients with a history of allergic reaction to IV contrast requiring steroid pre-treatment should have baseline and subsequent tumor assessments performed using MRI
    3. The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed
  26. Received anti-cancer therapy (medical agents or radiation) within 3 weeks prior to study Cycle 1, Day 1. However the following are allowed:

    a. Palliative radiotherapy for bone metastases > 2 weeks prior to Cycle 1, Day 1

  27. A history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator
  28. Known psychiatric or substance abuse disorders that would interfere with cooperation and the requirements of the trial
  29. Received a live vaccine within 30 days of planned start of study therapy, or is expected to receive such a vaccine while on therapy

    a. Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

  30. Any reason why, in the opinion of the investigator, the patient should not participate

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03409198

Contact: Jon Amund Kyte, MD PhD 22934000 ext +47 jonky@ous-hf.no
Contact: Bjørn Naume, MD PhD 22934000 ext +47 bjorn.naume@medisin.uio.no

Soerlandet Hospital HF Kristiansand Not yet recruiting
Kristiansand, Norway
Contact: Christian Kersten, MD         
Oslo University Hospital Recruiting
Oslo, Norway
Contact: Jon Amund Kyte, M.D.-Ph.D.    +4722934000    Jon.Amund.Kyte@rr-research.no   
Principal Investigator: Jon Amund Kyte, M.D.-Ph.D.         
Sub-Investigator: Bjørn Naume, M.D.-Ph.D.         
Stavanger University Hospital Not yet recruiting
Stavanger, Norway, 4011
Contact: Bjørnar Gilje, MD         
Sponsors and Collaborators
Oslo University Hospital
Bristol-Myers Squibb
Helse Stavanger HF
Helse Sor-Ost
Sorlandet Hospital HF
Principal Investigator: Jon Amund Kyte Oslo University Hospital

Responsible Party: Jon Amund Kyte, Principal Investigator, Oslo University Hospital
ClinicalTrials.gov Identifier: NCT03409198     History of Changes
Other Study ID Numbers: ICON CA209-9FN
First Posted: January 24, 2018    Key Record Dates
Last Update Posted: March 12, 2018
Last Verified: March 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Jon Amund Kyte, Oslo University Hospital:

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Liposomal doxorubicin
Antibodies, Monoclonal
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors